Alzheimer's disease (AD) is the most common cause of dementia in elderly populations throughout the world with more than 35 million people affected, and is projected to rise to 115 million by 2050 if effective therapeutics are not developed (Barnes and Yaffe, 2011). This age-related neurodegenerative disorder is pathologically characterized by amyloid β (Aβ)-containing senile plaques, neurofibrillary tangles, and synapse loss in the brain (Selkoe 2001). Although it is clear that AD is a degenerative disorder, the role of the immune system is prominent (reviewed in Britschgi and Wyss-Coray 2007). In AD, toxic Aβ peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain (de la Torre 2002; Deane and Zlokovic 2007), increasing their permeability (Nagababu et al 2009), and promoting transfer of T lymphocytes into brain (Farkas et al 2003). Macrophages/microglia ingest Aβ and are key players for Aβ clearance (Majumdar et al 2008; Mildner et al 2007; Simard et al 2006). Neutrophils also infiltrate into AD brain by virtue of blood brain barrier disruption (Stamatovic et al 2005).
Despite considerable effort, there neither a cure for AD, nor even a clinical test to reliably establish the diagnosis with certainty; post-mortem examination of brain tissue is currently the only certain way to confirm the diagnosis of AD. In fact, current diagnostic criteria have “Probable AD” as the category with the highest certainty (McKhann et al 2011), reflecting the limitations in ante-mortem diagnosis. A simple and reliable test would be important for several reasons: therapeutic trials will be more reliable if enrolled subjects have a definitive diagnosis, allowing a more homogeneous population to be studied. Milder cases of dementia (mild cognitive impairment), where diagnostic criteria for AD are not yet met, could be correctly classified as early AD vs. other causes (e.g. vascular), allowing better prognostication and institution of proper treatment, once this becomes available.
From a population health perspective, given that biochemical changes in AD brain (e.g. amyloid deposition) begin years to perhaps decades before clinical symptoms, it may be possible to detect early pre-clinical disease and institute preventive measures when available. Thus, development of an inexpensive, non-invasive, rapid test for AD is of paramount importance as the developed world braces for this inevitable epidemic.
Much effort has gone into developing biomarkers to support an AD diagnosis. In the blood, focus has been on measuring Aβ levels in the plasma. This has not proved reliable, as levels of Aβ40, Aβ42, or ratios of the two, cannot reliably separate healthy controls from AD patients (Thambisety and Lovestone 2010). Other approaches include proteornics analysis of plasma, but this is expensive, complex, not amenable to high throughput assays, and remains experimental. CSF analysis of Aβ and (phosphorylated) tau levels has stronger predictive value (van Rossum et al 2012; Senanaron et al 2012), but compared to blood is invasive and unlikely to become routine outside of formal research trials. Imaging markers (MRI, fMRI, FDG-PET, amyloid-PET) (Jack 2012; Matsuda and lmabayashi 2012) are all more expensive, not universally available, and are either non-specific (MRI) or highly specialized and available in only a few centers (e.g, amyloid-PET). Therefore, a simple and inexpensive blood test to diagnose AD and AD-related mild cognitive impairment that will progress to AD, is highly desirable. An ability to perform detection from small samples of human blood would be a tremendous improvement over current methods, and pave the way for developing a simple, rapid high-throughput screening method. Such methods would also be applicable to other diseases characterized by abnormal protein aggregation.